Protein kinase is considered a drug target as important as GPCR (G protein-coupled receptor). Abnormal activation of protein kinase is related to a number of diseases associated with cell overgrowth. Examples thereof include inflammatory and proliferative diseases, namely, what is called an overgrowth disorder, such as tumor, rheumatoid arthritis, cardiac disease, neurotic disease, psoriasis, asthma, angiogenesis and intravascular smooth muscle growth in postoperative stenosis or restenosis. Abnormality in protein kinase is said to be directly and indirectly involved in 400 kinds of human diseases, and therefore, once the activity of protein kinase can be controlled, various diseases are considered to be effectively treated. However, there are only a few compounds marketed as pharmaceutical products (non-patent reference 1).
It has been clarified that a protein phosphorylation reaction is extremely important for the mitotic progress of the cells causing cancer, genetic disease and the like, where a series of serine/threonine kinases called mitotic protein kinases play the role. Mitotic protein kinase phosphorylate substrate of various proteins at particular timing and site, whereby accurate mitosis proceeds. However, once the control thereof collapses, abnormality occurs in various events in the M-phase such as chromosome separation, causing radical character change of the cells. One of those mitotic protein kinases is aurora kinase. Aurora kinase is a highly-preserved serine/threonine kinase, which is expressed in the M phase of the cell cycle, and therefore, is considered an important enzyme for the progress of the M phase. It is highly preserved from yeast to human. There are human homologues of aurora 1-3: aurora 2 kinase and aurora 1 kinase are ubiquitously present in various cells but aurora 3 kinase is localized in testis. A gene encoding aurora 2 kinase is present on the long arm of chromosome 20, and this region relates to many cancers. The significance of the kinase family in the M phase has also been suggested by a function inhibitory experiment of aurora 2 kinase homologous gene using yeast, Drosophila and Caenorhabditis elegans (non-patent reference 2 and non-patent reference 3).
In addition, there have been clarified as facts that aurora 2 kinase is overexpressed in many cancers (non-patent reference 4, non-patent reference 5, non-patent reference 6, non-patent reference 7, non-patent reference 8, non-patent reference 9 and non-patent reference 10) and experimental overexpression of aurora 2 kinase in normal cell results in the cell showing a sign of malignant transformation (non-patent reference 11).
Furthermore, it has been documented that a treatment of human proliferative cell lines with antisense oligonucleotide suppresses expression of aurora 2 kinase, thus inhibiting growth of the cell (patent reference 1). This is considered to suggest that abnormal cell growth can be suppressed by the inhibition of aurora 2 kinase activity, which is useful for the treatment of a number of diseases associated with abnormal cell growth, such as cancer.
Some low molecular weight compounds inhibiting Aurora 2 kinase have been reported in patent reference and the like. For example, patent reference 2, patent reference 3, patent reference 4, patent reference 5, patent reference 6, patent reference 7, non-patent reference 12, non-patent reference 13 and non-patent reference 14 can be mentioned.
In addition, there are many reports relating to the involvement of aurora 1 kinase in cancer. For example, non-patent reference 15, non-patent reference 16, non-patent reference 17 can be mentioned. In the M-phase of cell cycle, duplicated chromosomes are equally separated into two daughter cells. In the M-phase, microtubules (tubulin polymerization products) form spindle bodies, which play a key role in the physical migration of chromosomes. Accordingly, tubulin polymerization and depolymerization play an important role in chromosome migration, and further, cell division. Paclitaxel, vincristine and the like widely used clinically as antitumor drugs are known to be pharmaceutical agents that act on tubulin and inhibit depolymerization and polymerization thereof (see non-patent references 18 and 19). It is considered that they consequently provoke M-phase arrest in the cell cycle (see non-patent reference 20), and show an antitumor action.    patent reference 1: JP-A-2002-95479    patent reference 2: WO2001-21595    patent reference 3: WO2002-22601    patent reference 4: WO2002-66461    patent reference 5: WO2003-55491    patent reference 6: WO2005-013996    patent reference 7: US-A-2005-0256102    non-patent reference 1: Irena Melnikova et al., Nature Reviews/Drug Discovery, vol. 3, pages 993-994, 2004    non-patent reference 2: David M. Glover et al., Cell, vol. 81, pages 95-105, 1995    non-patent reference 3: Daniela Berdnik et al., Current Biology, vol. 12, pages 640-647, 2002    non-patent reference 4: Hongyi Zhou et al., Nature Genetics, vol. 20, pages 189-193, 1998    non-patent reference 5: Takuji Tanaka et al., Cancer Research, vol. 59, pages 2041-2044, 1999    non-patent reference 6: C. Sakakura et al., British Journal of Cancer, vol. 84, pages 824-831, 2001    non-patent reference 7: Subrata Sen et al., Journal of the National Cancer Institute, vol. 94, pages 1320-1329, 2002    non-patent reference 8: Donghui Li et al., Clinical Cancer Research, vol. 9, pages 991-997, 2003    non-patent reference 9: Yung-Ming Jeng et al., Clinical Cancer Research, vol. 10, pages 2065-2071, 2004    non-patent reference 10: Sangeeta Rojanala et al., Molecular Cancer Therapeutics, vol. 3, No. 4, pages 451-457, 2004    non-patent reference 11: James R. Bischoff et al., EMBO Journal, vol. 17, pages 3052-3065, 1998    non-patent reference 12: Elizabeth A. Harrington et al., Nature Medicine, vol. 10, No. 3, pages 262-267, 2004    non-patent reference 13: Nicolas Keen et al., Nature Reviews Cancer, vol. 4, pages 927-936, 2004    non-patent reference 14: Daniele Faucelli et al., J. Med. Chem, vol. 48, pages 3080-3084, 2005    non-patent reference 15: Adams et al., Chromsoma, vol. 110, No. 2, pages 65-74, 2001    non-patent reference 16: W. Fischle et al., Nature, vol. 438, pages 1116-1122, 2005    non-patent reference 17: T. Hirota et al., Nature, vol. 438 pages 1176-1180, 2005    non-patent reference 18: Manfredi J. J.; Parness J.; Horwitz S. B. J. Cell Biol. 1982, 94, 688-696.    non-patent reference 19: Durko I.; Juhasz A. Neurochem. Res. 1990, 15, 1135-1139.    non-patent reference 20: Schiff P. B.; Fant J.; Horwitz S. B. Nature 1979, 227(5698), 665-667.